Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders.
Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders.
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DOI：
10.1002/jcph.92
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发表时间：
2013-07
影响因子：
2.9
通讯作者：
Scharschmidt, B. F.
中科院分区：
文献类型：
--
作者：
Monteleone, Jon P. R.;Mokhtarani, M.;Diaz, G. A.;Rhead, W.;Lichter-Konecki, U.;Berry, S. A.;LeMons, C.;Dickinson, K.;Coakley, D.;Lee, B.;Scharschmidt, B. F.
苯丁酸钠和苯丁酸甘油介导尿素循环障碍（UCDs）患者尿中苯乙酰谷氨酰胺（PAGN）形式的废氮排泄以尿素合成受损和高氨血症为特征的罕见遗传性疾病。苯丁酸钠被批准用于UCD治疗；苯基丁酸甘油的发展为表征这两种化合物的药代动力学（PK）提供了机会。人群PK模型的建立使用了4个II/III期试验的数据，这些试验总共招募了2个月至72岁的患者。剂量模拟特别关注苯乙酸（PAA），它与非ucd人群的不良事件有关。最后的模型描述了这两种药物在血浆和尿液中的代谢物水平，其特征是：(a)苯丁酸（PBA）对PAA和/或PAGN的部分系统前代谢，(b) PBA吸收较慢，与苯基丁酸甘油的系统前转化较大，(c)两种药物的PAA到PAGN的饱和转化相似的系统处理，以及(d)体表面积（BSA）作为年龄相关PK差异的重要协变量。剂量模拟显示，两种药物均给予摩尔当量PBA剂量后，PAA暴露相似，基于BSA的年轻患者PAA暴露更高。
Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data from four Phase II/III trials that collectively enrolled patients ages 2 months to 72 years. Dose simulations were performed with particular attention to phenylacetic acid (PAA), which has been associated with adverse events in non-UCD populations. The final model described metabolite levels in plasma and urine for both drugs and was characterized by (a) partial presystemic metabolism of phenylbutyric acid (PBA) to PAA and/or PAGN, (b) slower PBA absorption and greater presystemic conversion with glycerol phenylbutyrate, (c) similar systemic disposition with saturable conversion of PAA to PAGN for both drugs, and (d) body surface area (BSA) as a significant covariate accounting for age-related PK differences. Dose simulations demonstrated similar PAA exposure following mole-equivalent PBA dosing of both drugs and greater PAA exposure in younger patients based on BSA.
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影响因子：
6.1
作者：
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通讯作者：
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通讯作者：
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